The Autism Spectrum Disorders (ASD) encompass a spectrum of disorders which include autism, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS), Aspergers disorder and Rett syndrome. The working hypothesis of this proposal is that individuals with ASD experience disturbances in the intricate interplay between genetic predisposition, environmental triggers and experience-mediated neuronal activity during a sensitive period of development, and that this leads to an altered program of gene expression. Thus the neurological disabilities that are characteristic of the disorder result from genetic variability in the processes of synaptic development, maturation, refinement, and connectivity that normally shape the brain, and from an environmental insult that perturbs normal experience-dependant synaptic development. This proposal offers a novel approach aimed at unraveling the genetic mechanisms, improving diagnosis, deciphering the interplay between environment and genetics, and developing rational approaches to therapy.